The goal of this multicenter study is to identify genetic risk factors that predispose to amyotrophic lateral sclerosis (ALS). Our focus will be to identify risk genes that predispose to sporadic ALS or ALS observed in small families and familial aggregates. We will also continue our collaborative study of dominantly inherited familial ALS. Our primary hypothesis is that multiple genetic factors predispose to the development of ALS, and our specific aims of this multicenter study will test this hypothesis. We aim to: (i) Improve our resources for genetic analysis by collecting clinical information and DNA from sporadic ALS patients and their parents and from familial ALS families. (ii) Test certain genes that are hypothesized to predispose to ALS, in sporadic cases of and in small familial and in familial aggregates (iii) Search for gene loci in small familial aggregates, unsuitable for conventional parametric linkage analysis by, non-parametric linkage technique. (iv) Use parametric linkage analysis to search for gene linkage in large familial ALS families that do not have mutations in the gene for Cu,Zn superoxide dismutase. This is the first large-scale study of genetic risk factors in ALS, and is only possible because of collaborative arrangement between four centers, Northwestern University Medical School, Massachusetts General Hospital, Duke University Medical Center and Vanderbilt University Medical Center. This study will identify additional genes that cause or predispose to ALS, and contribute to the understanding of the biology of the motor neuron. This study will be a major contribution to our ultimate goal, which is to develop rational therapy for ALS based on the causes and mechanism of disease.